CN105461774B - Preparation method of sofosbuvir - Google Patents
Preparation method of sofosbuvir Download PDFInfo
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Abstract
The invention relates to a preparation method of sofosbuvir, in particular to a synthesis method of a compound sofosbuvir (sofosbuvir) for treating mammal hepatitis C, which comprises the steps of reacting a raw material A with a raw material B under the action of a proper Lewis acid and a proper alkali to obtain a mixed solution of a target product C, and carrying out chromatographic analysis, extraction, crystallization and pulping on the mixed solution of the product C to obtain a pure product C. The invention surprisingly discovers key factors which can obviously influence the preparation effect of the compound C and promotes the effect maximization of the preparation process, thereby ensuring that the compound C can efficiently realize industrial production with high quality, being suitable for the market demand of products, reducing the production cost and benefiting patients.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a preparation method of Sofosbuvir.
Background
Viral hepatitis C, abbreviated as hepatitis C and hepatitis C, is a viral hepatitis caused by Hepatitis C Virus (HCV) infection, and is mainly transmitted by blood transfusion, acupuncture, drug inhalation and the like, according to the statistics of the world health organization, the global HCV infection rate is about 3%, about 1.8 hundred million people are estimated to be infected with HCV, and about 3.5 ten thousand cases of new hepatitis C are generated every year. Hepatitis c is a global epidemic that can lead to chronic inflammatory necrosis and fibrosis of the liver, and some patients can develop cirrhosis and even hepatocellular carcinoma (HCC). The mortality rate associated with HCV infection (death from liver failure and hepatocellular carcinoma) will continue to increase over the next 20 years, posing significant health and life risks to the patient and becoming a serious social and public health problem.
HCV virions are spherical, less than 80nm in diameter (36-40 nm in hepatocytes and 36-62nm in blood), are single-stranded positive-strand RNA viruses, surround a lipid-containing envelope outside the nucleocapsid, and have spikes on the envelope. Only three in vitro cell culture systems of Huh7, Huh7.5 and Huh7.5.1 are used for HCV, and chimpanzees can be infected with HCV, but the symptoms are relatively mild. HCV-RNA consists of approximately 9500-10000 bp, 319-341bp for the 5 'and 3' non-coding regions (NCR), and 27-55bp for the 5 'and 3' regions, respectively, and contains several forward and reverse repeats, which may be involved in gene replication. Immediately downstream of the 5' noncoding region is an Open Reading Frame (ORF) in which the genome is arranged in the order 5' -C-E1-E2-p7-NS2-NS3-NS4-NS5-3', which encodes a polyprotein precursor of approximately 3014 amino acids in length that can be cleaved by the host cell and viral autoproteases into 10 viral proteins, including three structural proteins, namely the nucleocapsid protein (or Core) with a molecular weight of 19KD and two glycoproteins (E1 protein with a molecular weight of 33KD, E2 protein with a molecular weight of 72 KD), p7 encodes an integral membrane protein that may function as an ion channel. The nonstructural protein portion includes NS2, NS3, NS4A, NS5A and NS5B, which are important to the life cycle of the virus. NS2 and NS3 have protease activity and are involved in the cleavage of viral polyprotein precursors. In addition, the NS3 protein also has helicase activity and is involved in unwinding HCV-RNA molecules to facilitate RNA replication, and the function of NS4 is unknown. NS5A is a phosphoprotein that interacts with a variety of host cell proteins and plays an important role in viral replication. NS5B has RNA-dependent RNA polymerase activity and is involved in HCV genome replication.
Before treatment it should be clear whether the liver disease of the patient is caused by HCV infection, and only patients with viral hepatitis c who have been diagnosed as positive for serum HCV rna require antiviral treatment. The most effective regimens currently recognized for antiviral therapy are: the long-acting interferon PEG-IFN alpha combined application of ribavirin is also a standard Scheme (SOC) approved by EASL for treating chronic viral hepatitis C, and the common IFN alpha or the combined therapy of compound IFN and ribavirin is superior to that of single IFN alpha. Polyethylene glycol (PEG) interferon alpha (PEG-IFN alpha) is an inactive and nontoxic PEG molecule crosslinked on IFN alpha molecules, so that the absorption and in-vivo clearance process after IFN alpha injection is delayed, the half-life period is long, and the effective blood concentration can be maintained after 1-time administration every week.
Triple therapy of direct acting antiviral Drug (DAA) protease inhibitor Boceprevir (BOC) or Telaprevir (TVR) in combination with interferon ribavirin was approved for clinical use in the united states in 5 months of 2011 and recommended for HCV-infected patients with genotype 1, which could improve the cure rate. Three times a day (every 7-9 hours) after a Boceprevir (BOC) meal, or three times a day (every 7-9 hours) after a Telaprevir (TVR) meal (non-low fat diet). During this period, the hcv rna should be monitored closely and if a virologic breakthrough occurs (serum hcv rna rises >1log after the lowest value), the protease inhibitor should be discontinued.
Sofosbuvir, giridg, was approved by the FDA in 2013 as part of a combination antiviral treatment regimen for the treatment of chronic hepatitis c infection. Sofosbuvir is an inhibitor of HCV NS5B RNA-dependent RNA polymerase that is essential for replication of the hepatitis c virus. Sofosbuvir is a novel process for the preparation of the nucleoside phosphoramidate (S) -isopropyl-2- ((S) - (((2R,3R,4R,5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphono) amino) propanoate which is an inhibitor of RNA-dependent RNA viral replication and is useful as an inhibitor of HCV NS5B polymerase, an inhibitor of HCV replication, and for the treatment of hepatitis C infections in mammals.
The drug is a nucleotide prodrug that is metabolized in the cell to form the pharmacologically active uracil analog triphosphate (GS-461203), which is incorporated into HCV RNA by NS5B polymerase and acts as a chain terminator. In a biochemical assay, GS-461203 inhibited polymerase activity from recombinant NS5B of HCV genes type 1b, 2a, 3a and 4a, with IC50 values ranging from 0.7 to 2.6. mu.M. GS-461203 is not an inhibitor of human DNA and RNA polymerase nor is it an inhibitor of mitochondrial RNA polymerase.
As indicated by Giliddi, Sovaldi can be used alone or in combination with ribavirin. As a traditional anti-infective drug, ribavirin is suitable for treatment of patients with type 2 and type 3 gene infections, and the infectors belonging to these two genotypes account for approximately 30% of patients with hepatitis c in the united states, while 70% of those with type 1 gene infections account for the greatest proportion in the united states, and interferon treatment is not suitable for these patients, but Sovaldi in combination with ribavirin and interferon can achieve certain therapeutic effects for this new anti-infective drug. In addition, the three-drug combination regimen described above can be used to treat this type of infection, although the proportion of those infected with the type 4 gene is minimal. Multiple studies have shown that girard's anti-infective drug has superior clearance rates and fewer adverse effects than current treatment regimens.
Disclosure of Invention
The object of the present invention is to provide a process for the preparation of the compound of formula (I), H1NMR data are shown in FIG. 1.
P*Denotes a chiral phosphorus atom
(1) Reacting a raw material A and a raw material B under the action of a proper Lewis acid and a proper base to obtain a mixed solution of a compound C; wherein LG in the structural formula of the raw material A represents a leaving group;
(2) carrying out post-treatment on the mixed solution of the compound C to obtain a pure compound C,
preferably, the post-treatment comprises chromatography, extraction, crystallization, and beating.
Preferably, the leaving group LG is selected from leaving groups of phenols, hydroxypyridine, hydroxyquinoline, hydroxytriazole, imidazole or naphthol compounds.
More preferably, when the leaving group LG is a phenol, the leaving group is selected from a pentafluorophenoxy group, a 4-nitrophenoxy group, a 2, 4-dinitrophenoxy group or a 4-chlorophenoxy group.
More preferably, when the leaving group LG is a hydroxypyridine, the leaving group is selected from 2-hydroxy-6-chloropyridine, 2-hydroxy-5-chloropyridine, 2-hydroxy-3-chloropyridine, 3-hydroxy-5-chloropyridine, 4-hydroxy-6-chloropyridine or 3-bromo-5-hydroxypyridine.
Preferably, the solvent used for the reaction is anhydrous THF.
Preferably, the lewis acid is substantially anhydrous.
More preferably, the lewis acid is selected from zinc chloride, zinc bromide, aluminum chloride or magnesium chloride.
Preferably, the base used in the reaction is substantially anhydrous.
More preferably, the base is selected from N, N-Diisopropylethylamine (DIEA), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine, potassium tert-butoxide or N-methylmorpholine.
Preferably, the ratio of the raw material A: the raw material ratio B: lewis acid: the molar ratio of the base is about 1.4-2.2: 1: 1.2-1.8: 1.2-1.8, preferably 2: 1: 1.6: 1.6.
preferably, the temperature of the reaction is controlled to be 45-60 ℃.
Further preferably, the preparation method of the present invention specifically comprises:
(1) putting the raw material A, the raw material B, the Lewis acid and the alkali into a reaction bottle, adding a proper amount of anhydrous THF, and reacting in an oil bath for at least 20 hours;
after the reaction is finished, cooling to room temperature;
adding a proper amount of ethyl acetate to dilute the reaction solution, and adding a proper amount of saturated NH4Quenching with a Cl solution, extracting, washing an organic phase with a proper amount of dilute acid, extracting, washing the organic phase with alkali, extracting, washing the organic phase with a buffer solution, extracting, washing the organic phase with a proper amount of saline water, and spin-drying the organic phase to obtain a first crude product of the compound C;
adding a proper amount of mixed solution of dichloromethane/toluene-1/1 into the obtained first crude product of the compound C, crystallizing, and filtering to obtain a second crude product of the compound C;
the second crude compound C thus obtained was slurried with a suitable amount of a mixed ethyl acetate/dichloromethane 1/5 solution to afford pure compound C.
Preferably, the buffer is an alkali carbonate/alkali bicarbonate buffer.
Further preferably, the preparation method of the invention comprises the following steps:
putting the raw material A, the raw material B, the Lewis acid and the alkali into a reaction bottle, adding 10V of anhydrous THF, and placing the mixture in an oil bath at the temperature of 55 ℃ for reaction for 20 hours;
detecting by TLC, completing the reaction, and naturally cooling to room temperature;
adding 20V ethyl acetate to dilute the reaction solution, and adding 20V saturated NH4Quenching with Cl solution, extracting, washing the organic phase with 20V diluted hydrochloric acid (0.5N), extracting, washing the organic phase with 2V saturated sodium bicarbonate, extracting, washing the organic phase with 2X 20V sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extracting, washing the organic phase with 2X 20V salt water, and spin-drying the organic phase to obtain a first crude product (oily substance) of C;
adding a mixed solution of 10V dichloromethane/toluene-1/1 to the obtained first crude product of C, crystallizing, and filtering to obtain a second crude product of C (white solid);
to the second crude product of C obtained was added a mixed solution of 10V ethyl acetate/dichloromethane-1/5 and slurried to give pure C.
The preparation method has the advantages that various influencing factors influencing the preparation of the compound C are searched, Lewis acid and common organic base are initiatively used as reaction auxiliaries to prepare the sofosbuvir, the Lewis acid activates phosphorus-oxygen double bonds through coordination, the steric hindrance of P chiral centers is reduced, the leaving of halogenated hydroxypyridine groups in the raw material A is facilitated, and the remaining fragments and the raw material B are subjected to nucleophilic substitution reaction. In the prior art, 2.1 equivalent of tert-butyl magnesium chloride is used to react with a raw material B at 0 ℃ to form an oxyanion with strong nucleophilic force, and then a nucleophilic substitution reaction is carried out to generate a finished product.
Compared with the route of the prior art, the invention has the following advantages:
1) the reaction condition is mild, the process is easy to control, flammable and explosive strong base such as tert-butyl magnesium chloride is avoided, and the reaction risk is reduced;
2) compared with the prior art, the method has the advantages that the production cost is low, and the Lewis acid and the organic base used in the method are low in price and easy to obtain;
3) the method is simple to operate, and the raw materials are added together at normal temperature and then heated for reaction, namely, the method of one pot is simpler, more convenient and more efficient compared with the prior art in which the raw materials are fed step by step at low temperature;
4) the invention has simple post-treatment, needs no neutralization of excessive strong alkali and discharges less waste per unit product. In conclusion, the method can achieve the effects of mild reaction, low cost, simple operation and environmental friendliness.
On the basis, the inventors further study and found that the preparation effect of the compound C can be better promoted by screening the leaving group of the compound A, and finally, the inventors selected various leaving groups with obvious effects.
Furthermore, the inventor selects proper Lewis acid and alkali by optimizing reaction conditions, and can further promote the effect maximization of the preparation process, thereby ensuring that the compound C can efficiently and high-quality realize industrial production, meeting the market demand of products, reducing the production cost and benefiting patients.
Drawings
FIG. 1 is (S) -isopropyl-2- ((S) - ((((2R, 3R,4R,5R) -5- (2, 4-dioxo-3, 4-dihydropyrimidin-1 (2H) -yl) -4-fluoro-3)Preparation of (E) -hydroxy-4-methyltetrahydrofuran-2-yl) methoxy) (phenoxy) phosphonyl) amino) propionate1HNMR (400MHz, DMSO) profile.
FIG. 2 is an HPLC chromatogram of a reaction of the raw material A1, the raw material B, zinc chloride and triethylamine in an oil bath at 55 ℃ for 20 hours.
FIG. 3 is an HPLC chromatogram of a reaction of A1, B, Zn chloride and N, N-Diisopropylethylamine (DIEA) in a 55 ℃ oil bath for 20 hours.
FIG. 4 is an HPLC chromatogram of a 20-hour reaction of starting material A1, starting material B, zinc chloride, and DBU in a 55 ℃ oil bath.
FIG. 5 is an HPLC chromatogram of a reaction of starting material A1, starting material B, zinc chloride and potassium tert-butoxide in an oil bath at 55 ℃ for 20 hours.
FIG. 6 is an HPLC chromatogram of a 20-hour reaction of starting material A1, starting material B, zinc chloride and N-methylmorpholine in a 55 ℃ oil bath.
FIG. 7 is an HPLC chromatogram of a reaction of A1, B, zinc bromide and N, N-Diisopropylethylamine (DIEA) in a 55 ℃ oil bath for 20 hours.
FIG. 8 is an HPLC chromatogram of a reaction of A1, B, aluminum chloride and N, N-Diisopropylethylamine (DIEA) in a 55 ℃ oil bath for 20 hours.
FIG. 9 is an HPLC chromatogram of a reaction of starting material A1, starting material B, magnesium chloride, and N, N-Diisopropylethylamine (DIEA) in a 55 ℃ oil bath for 20 hours.
Detailed Description
In order to further explain the technical solutions and effects of the present invention, the present invention will be described in detail with reference to specific embodiments, but the present invention is not limited to the specific embodiments.
Example 1
Mixing 1.59g A1,0.52g B,0.44g ZnCl2And 0.33g of triethylamine are put into a 50mL single-mouth bottle, 10mL of anhydrous THF is added as a solvent, the mixture is stirred in an oil bath at 55 ℃ for 20 hours, the completion of the reaction is detected by TLC, the mixture is naturally cooled to room temperature, and 20mL of ethyl acetate is addedThe reaction solution was diluted, and 20mL of saturated NH was added4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.31 g, mass yield: 59 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are shown in FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 2.
Wherein, the A1 compound can be prepared by reacting di-halo-phenyl phosphate, isopropyl alaninate as a compound in a formula B and hydroxypyridine under the action of alkali.
Example 2
Mixing 1.59g A1,0.52g B,0.44g ZnCl2And 0.42g DIEA into a 50mL single-neck flask, adding 10mL anhydrous THF as solvent, stirring in 55 deg.C oil bath for 20 hr, detecting reaction completion by TLC, naturally cooling to room temperature, adding 20mL ethyl acetate to dilute the reaction solution, adding 20mL saturated NH4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.42 g, mass yield: 80 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6)(ppm)11.53(s,1H),7.57(d,J＝3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t,J＝6.4Hz,2H),5.86(d,J＝3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC profile of the reaction solution is shown in fig. 3.
Example 3
Mixing 1.59g A1,0.52g B,0.44g ZnCl2And 0.8g of DBU are put into a 50mL single-neck bottle, 10mL of anhydrous THF is added as a solvent, the mixture is stirred in an oil bath at 55 ℃ for 20 hours, TLC is used for detecting the completion of the reaction, the temperature is naturally reduced to the room temperature, 20mL of ethyl acetate is added for diluting the reaction solution, and 20mL of saturated NH is added4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.38 g, mass yield: 73 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 4.
Example 4
Mixing 1.59g A1,0.52g B,0.44g ZnCl2And 0.36g of potassium tert-butoxide are put into a 50mL single-neck flask, 10mL of anhydrous THF is added as a solvent, the mixture is stirred in an oil bath at 55 ℃ for 20 hours, TLC is used for detecting the completion of the reaction, the temperature is naturally reduced to room temperature, 20mL of ethyl acetate is added for diluting the reaction solution, and 20mL of saturated NH is added4Quenching with Cl solution, extracting, washing the organic phase with 20mL of dilute hydrochloric acid (0.5N), extracting, washing the organic phase with 20mL of saturated sodium bicarbonate, extracting, washing the organic phase with 2X 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extracting, washing the organic phase with 2X 20mL of common salt, spin-drying the organic phase, crystallizing with 5mL of a mixed solution of dichloromethane/toluene-1/1, filtering, and washing the solid with 5mL of ethyl acetateThe mixed solution of ester/dichloromethane ═ 1/5 was slurried to give C0.21 g, mass yield: 40 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 5.
Example 5
Mixing 1.59g A1,0.52g B,0.44g ZnCl2And 0.3g of N-methylmorpholine into a 50mL single-neck flask, adding 10mL of anhydrous THF as a solvent, stirring in a 55 ℃ oil bath for 20 hours, detecting the completion of the reaction by TLC, naturally cooling to room temperature, adding 20mL of ethyl acetate to dilute the reaction solution, adding 20mL of saturated NH4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.18 g, mass yield: 35 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 6.
Example 6
Mixing 1.59g A1,0.52g B,0.72g ZnBr2And 0.42g DIEA into a 50mL single-neck flask, adding 10mL anhydrous THF as solvent, stirring in 55 deg.C oil bath for 20 hr, detecting reaction completion by TLC, naturally cooling to room temperature, adding 20mL ethyl acetate to dilute the reaction solution, adding 20mL saturated NH4Quenching with Cl solution, extracting, and organic phaseWashing with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of a buffer solution of sodium carbonate (5%) and sodium bicarbonate (5%), extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with a mixed solution of 5mL of dichloromethane/toluene ═ 1/1, filtration, and beating of the solid with a mixed solution of 5mL of ethyl acetate/dichloromethane ═ 1/5 gave C0.36 g, mass yield: and 69 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 7.
Example 7
Mixing 1.59g A1,0.52g B,0.43gAlCl3And 0.42g DIEA into a 50mL single-neck flask, adding 10mL anhydrous THF as solvent, stirring in 55 deg.C oil bath for 20 hr, detecting reaction completion by TLC, naturally cooling to room temperature, adding 20mL ethyl acetate to dilute the reaction solution, adding 20mL saturated NH4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.29 g, mass yield: 56 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC map of the reaction solution is shown in fig. 8.
Example 8
Will 1.59g A1,0.52g B,0.31gMgCl2And 0.42g DIEA into a 50mL single-neck flask, adding 10mL anhydrous THF as solvent, stirring in 55 deg.C oil bath for 20 hr, detecting reaction completion by TLC, naturally cooling to room temperature, adding 20mL ethyl acetate to dilute the reaction solution, adding 20mL saturated NH4Quenching with Cl solution, extraction, washing of the organic phase with 20mL of dilute hydrochloric acid (0.5N), extraction, washing of the organic phase with 20mL of saturated sodium bicarbonate, extraction, washing of the organic phase with 2 × 20mL of sodium carbonate (5%) and sodium bicarbonate (5%) buffer solution, extraction, washing of the organic phase with 2 × 20mL of brine, spin-drying of the organic phase, crystallization with 5mL of a mixed solution of dichloromethane/toluene ═ 1/1, filtration, beating of the solid with 5mL of a mixed solution of ethyl acetate/dichloromethane ═ 1/5, C0.26 g, mass yield: 50 percent. Wherein of compound C1HNMR (400MHz, DMSO) spectra are consistent with FIG. 1,1HNMR(400MHz,DMSO-d6) (ppm)11.53(s,1H),7.57(d, J ═ 3.8Hz,1H),7.40-7.36(m,2H),7.24-7.17(m,3H),6.06(t, J ═ 6.4Hz,2H),5.86(d, J ═ 3.2Hz,1H),5.55(d, J ═ 4.2Hz,1H),4.89-4.83(m,1H),4.36-4.22(m,1H),4.03-4.00(m,1H),3.87-3.83(m,1H),3.82-3.35(m,2H),1.32-1.23(m,6H),1.15(d, J ═ 3.2Hz,6H), and the HPLC of the reaction solution is shown in fig. 9.
Through exploration and screening of the preparation process, the inventor surprisingly finds that the Lewis acid serving as a reaction auxiliary agent can bring about non-significant technical progress, further, the yield of the compound C can be better promoted through screening of a special leaving group, and the inventor verifies and compares other reaction conditions, so that the effect of the preparation process is not substantially influenced.
Claims (12)
1. A method of preparing a compound of formula C:
whereinP*Representing a chiral phosphorus atom, the method comprising:
(1) adding the raw material A, the raw material B, the Lewis acid and the alkali into the same reaction vessel, and reacting the raw materials under the action of the Lewis acid and the alkali through 'one-pot boiling' to obtain a mixed solution of a compound C; wherein LG in the structural formula of the raw material A represents a leaving group;
(2) the mixed solution of the compound C is subjected to post-treatment to obtain a pure compound C,
the Lewis acid is selected from zinc chloride, zinc bromide, aluminum chloride or magnesium chloride;
the base is selected from N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, potassium tert-butoxide or N-methylmorpholine;
the leaving group is selected from 2-hydroxy-6-chloropyridine, 2-hydroxy-5-chloropyridine, 2-hydroxy-3-chloropyridine, 3-hydroxy-5-chloropyridine, 4-hydroxy-6-chloropyridine or 3-bromo-5-hydroxypyridine.
2. The process as claimed in claim 1, wherein the solvent used in the reaction is anhydrous THF.
3. The method of claim 1, wherein the lewis acid is anhydrous.
4. The process of claim 1, wherein the base used in the reaction is anhydrous.
5. The method of claim 1, wherein the feed stock A: raw material B: lewis acid: the molar ratio of the alkali is 1.4-2.2: 1: 1.2-1.8: 1.2-1.8.
6. The method of claim 5, wherein the feed A: raw material B: lewis acid: the molar ratio of the base is 2: 1: 1.6: 1.6.
7. the process according to claim 1, wherein the temperature of the reaction is controlled at 45-60 ℃.
8. The method of claim 1, wherein the post-treatment process comprises chromatography, extraction, crystallization, slurrying.
9. The method according to claim 1, which method comprises in particular:
(1) putting the raw material A, the raw material B, the Lewis acid and the alkali into a reaction bottle, adding a proper amount of anhydrous THF, and reacting in an oil bath for at least 20 hours;
after the reaction is finished, cooling to room temperature;
adding a proper amount of ethyl acetate to dilute the reaction solution, adding a proper amount of saturated NH4Cl solution to quench, extracting, washing an organic phase with a proper amount of diluted acid, extracting, washing an organic phase with alkali, extracting, washing an organic phase with a buffer solution, extracting, washing an organic phase with a proper amount of salt water, and spin-drying the organic phase to obtain a first crude product of the compound C;
adding a proper amount of dichloromethane/toluene mixed solution into the obtained first crude product of the compound C, crystallizing, and filtering to obtain a second crude product of the compound C;
and adding a proper amount of mixed solution of ethyl acetate/dichloromethane into the obtained second crude product of the compound C, and pulping to obtain the pure compound C.
10. The process according to claim 9, wherein the volume ratio of dichloromethane/toluene is 1/1 and the volume ratio of ethyl acetate/dichloromethane is 1/5.
11. The method according to claim 9, characterized in that the buffer solution is an alkali carbonate/alkali bicarbonate buffer.
12. The method of claim 9, wherein the method comprises:
(1) putting the raw material A, the raw material B, the Lewis acid and the alkali into a reaction bottle, adding a proper amount of anhydrous THF, and reacting in an oil bath for at least 20 hours;
after the reaction is finished, cooling to room temperature;
adding a proper amount of ethyl acetate to dilute the reaction solution, adding a proper amount of saturated NH4Cl solution to quench, extracting, washing an organic phase with a proper amount of dilute acid, extracting, washing an organic phase with a proper amount of saturated sodium bicarbonate, extracting, washing an organic phase with a sodium carbonate and sodium bicarbonate buffer solution, extracting, washing an organic phase with a proper amount of brine, and spin-drying the organic phase to obtain a first crude product of the compound C;
adding a proper amount of dichloromethane/toluene mixed solution into the obtained first crude product of the compound C, crystallizing, and filtering to obtain a second crude product of the compound C, wherein the volume ratio of dichloromethane/toluene is 1/1;
and adding a proper amount of mixed solution of ethyl acetate/dichloromethane into the obtained second crude product of the compound C, and pulping to obtain the pure compound C, wherein the volume ratio of ethyl acetate/dichloromethane is 1/5.
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| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| WO2014076490A1 (en) * | 2012-11-16 | 2014-05-22 | University College Cardiff Consultants Limited | Process for preparing nucleoside prodrugs |
| CN103848876A (en) * | 2013-03-25 | 2014-06-11 | 安徽贝克联合制药有限公司 | Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug |
| CN106661074A (en) * | 2014-07-31 | 2017-05-10 | 桑多斯股份公司 | Synthesis of phosphoramidates |
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| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| WO2014076490A1 (en) * | 2012-11-16 | 2014-05-22 | University College Cardiff Consultants Limited | Process for preparing nucleoside prodrugs |
| CN103848876A (en) * | 2013-03-25 | 2014-06-11 | 安徽贝克联合制药有限公司 | Nucleoside phosphamide prodrug as well as preparation method and application of nucleoside phosphamide prodrug |
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